Studies from our laboratory have shown that as compared to gingival tissue from non-diabetic patients, gingival tissue from diabetic patients displays accumulation of nonenzymatically glycated proteins in the vessel wall and connective tissues. These glycated proteins, (Advanced Glycation Endproducts (AGEs)), induce cross-linking, thereby altering basement membrane and connective tissue structure and enable the glycated adducts to interact with a specific receptor (Receptor for AGE or RAGE) present on endothelial cells (ECs) and mononuclear phagocytes (MPs). Engagement of RAGE by AGEs results in induction of oxidant stress and changed cellular properties. On the EC, this includes induction of vascular cell adhesion molecule-1 (VCAM-1), expression of cytokines and vascular hyperpermeability. On MPs, this includes expression of cytokines. AGEs immobilized in the subendothelial matrix inhibit MP migration, blocking their transit through the tissue and resulting in establishment of a locus of sustained inflammatory activity . These observations suggest the following hypothesis underlying the accelerated periodontal disease (PD) in patients with diabetes: AGEs in diabetic gingiva stimulate ECs via RAGE, enhance expression of VCAM-1, and increase leakage of plasma; MPs attracted to the gingiva are immobilized and stimulated by AGEs, also via their interaction with RAGE, resulting in sustained local production of cytokines. These changes prime the gingiva for an exaggerated proinflammatory response to periodontal pathogens, ultimately, leading to resorption of non- mineralized connective tissue and bone. Our specific aims are: (1) to determine the effect of immobilized AGEs in diabetic gingiva on ECs and MPs, focussing on the role of RAGE, (2) to determine the contribution of AGE-RAGE interaction in the development of accelerated PD in murine models of diabetes by studying the biochemical and cellular events involved in the pathogenesis of PD, and 3) to assess the effect of RAGE blockade and antioxidants in the development of PD in diabetes. To delineate the role of RAGE in accelerated diabetic PD, studies will be performed in mice in whom the expression of RAGE has been enhanced or deleted. The goal of these studies is to determine the relationship in diabetes of the deposition of AGEs and expression of RAGE in gingiva, the activation state of the vasculature and infiltrating host effector cells to progressive PD. These studies should identify possible therapeutic approaches directed at these targets.